The B-cell specific Moloney murine leukemia virus integration site 1 (Bmi-1) gene, is a member of the Polycomb group (PcG) of transcriptional repressors, was first identified as a pro-oncogene and subsequently discovered to be a necessary regulator of hematopoietic stem cell (HSC) self-renewal (Park et al., 2003, Nature. 423:302-305; Lessard et al., 2003, Nature 423:255-260). Park and colleagues found that Bmi-1 is highly expressed in purified mouse and human HSCs and that the absence of Bmi-1, as demonstrated by Bmi-1 knockout mice, results in the progressive loss of all hematopoietic lineages (Park et al., 2003, Nature. 423:302-305). Furthermore, the transplantation of Bmi-1−/− day 14.5 fetal liver cells into lethally irradiated normal mice, demonstrated that the cells were unable to reconstitute myeloid cells, B cells, and T cells because Bmi-1−/− HSCs were unable to renew (Park et al., 2003, Nature. 423:302-305).
In addition to Bmi-1's role in HSC self renewal, it was found that Bmi-1 transgene expression induced lymphoma in mice (Haupt et al., 1993, Oncogene. 11:3161-3164). It was also discovered that Bmi-1 overexpression is found in many tumor types, including myeloid leukemia, medulloblastoma, neuroblastoma, colorectal cancer, lung cancer, and prostate cancer, and increases with malignancy (Sawa et al., 2005, Int J. Hematol. 82:42-47; Wiederschain et al., 2007, Mol Cell Biol. 27(13):4968-4967; Cui et al., 2007, Am J. Pathol. 170:130-1378; Reinisch et al., 2006, Histol Histopathol. 21:1143-1149; Breuer et al., 2005, Lung'Cancer. 48:299-306; Kim et al., 2004, Breast. 13:383-388; Glinsky et al., 2005, J. Clin. Invest. 115:1503-1521). Loss of Bmi-1 in various cancerous human cell lines via Bmi-1 specific RNA interference (RNAi) was shown to lead to acute cell death and growth inhibition, whereas loss of Bmi-1 in various normal progenitor or stem cell types was shown to lead to only moderate growth inhibition and not significant cell death (Liu et al., 2006, Oncogene. 25:4370-4375). Thus, Bmi-1 and Bmi-1 is necessary for the survival of cancer cells but has minimal effect on the survival of normal cells.